Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes
Authors: Deborah J. Wexler, Ian H. de Boer, Alokananda Ghosh, Naji Younes, Ionut Bebu, Silvio E. Inzucchi, Janet B. McGill, Sunder Mudaliar, David Schade, Michael W. Steffes, William V. Tamborlane, Meng H. Tan, Faramarz Ismail-Beigi, Jill P. Crandall, Melissa Diane McKee, Stephanie Beringher-Massera, Janet Brown-Friday, Entila Xhori, Keisha Ballentine-Cargill, Sally Duran, Hayley Estrella, Susana Gonzalez de la torre, Jennifer Lukin, Lawrence Phillips, Elizabeth Burgess, Darin Olson, Mary Rhee, Peter Wilson, Tasha Stephanie Raines, Johanna Boers, Julie Costello, Maxine Maher-Albertelli, Radhika Mungara, Louise Savoye, CarolAnn White, Chona Gullett, Leah Holloway, Folayan Morehead, Saranjit Person, Mabil Sibymon, Sridhar Tanukonda, Cynthia Adams, April Ross, Ashok Balasubramanyam, Ruchi Gaba, Erica Gonzalez, Adrienne Ideozu, Julizza Jimenez, Gabriela Montes, Charlyne Wright, Priscilla Hollander, Erin Roe, Analyn Jackson, Ashley Smiley, Polly Burt, Lorie Estrada, Kris Chionh, Faramarz Ismail-Beigi, Corinna Falck-Ytter, Laure Sayyed Kassem, Ajay Sood, Margaret Tiktin, Bethany Cramer, Jacalyn Iacoboni, Maria V. Kononets, Tanya Kulow, Cynthia Newman, Katherine A. Stancil, Cristina Sanders, Lisa Tucker, Amanda Werner, Adrienne Krol, Gloria McPhee, Christine Patel, Linda Colosimo, Audrey Maxwell, Robin Goland, James Pring, Lucia Alfano, Patricia Kringas, Camille Hausheer, Jessica Tejada, Kelly Gumpel, Amanda Kirpitch, Harvey Schneier, Jennifer B. Green, Hiba AbouAssi, Ranee Chatterjee, Mark N. Feinglos, Jennifer English Jones, Shubi A. Khan, Jeanne B. Kimpel, Ronna P. Zimmer, Mary Furst, Barbara M. Satterwhite, Connie R Thacker, Kathryn Evans Kreider, Cary N Mariash, Kieren J. Mather, Heba M Ismail, Amale Lteif, Maureen Mullen, Tonya Hamilton, Nick Patel, Gabriela Riera, Marcia Jackson, Vivian Pirics, Devin Howard, Danielle Aguillar, Sloan Hurt, Richard Bergenstal, Anders Carlson, Thomas Martens, Mary Johnson, Renae Hill, Jamie Hyatt, Connie Jensen, Marcia Madden, Dianna Martin, Holly Willis, Wanda Konerza, Shoua Yang, Rebecca Passi, Kathleen Kleeberger, Stephen Fortmann, Michael Herson, Karen Mularski, Harry Glauber, James Prihoda, Britt Ash, Christina Carlson, Phyllis Anne Ramey, Emily Schield, Britta Torgrimson-Ojerio, Kathy Arnold, Bryan Kauffman, Elease Panos, Samantha Sahnow, Kristi Bays, Jennifer Cook, Jennifer Gluth, Debra Ghioni, Katrina Schell, Jennifer Criscola, Camille Friason, Suzi Jones, Sergey Nazarov, Joshua Barzilay, Negah Rassouli, Rachel Puttnam, Olubukola Ojoawo, Roslin Nelson, Michelle Curtis, Bonita Hollis, Cynthia Sanders-Jones, Kia Stokes, Zakiah El-Haqq, Abby Kolli, Tu Tran, Deborah Wexler, Mary Larkin, James Meigs, Brittany Chambers, Amy Dushkin, Gianna Rocchio, Mike Yepes, Barbara Steiner, Hilary Dulin, Melody Cayford, Andrea DeManbey, Mallory Hillard, Kimberly Martin, Nopporn Thangthaeng, Lindsey Gurry, Raquel Kochis, Elyse Raymond, Valerie Ripley, Christine Stevens, Jean Park, Vanita Aroda, Adline Ghazi, Michelle Magee, Ann Ressing, Amy Loveland, Mia Hamm, Maria Hurtado, Alexander Kuhn, Jayme L. Leger, Lumanti Manandhar, Florence Mwicigi, Osirelis Sanchez, Theresa Young, Rajesh Garg, Victoria Lagari-Libhaber, Hermes J Florez, Willy M Valencia, Jennifer Mark, Sabina Casula, Lisset Oropesa-Gonzalez, Lisa Hue, Alain Cuadot, Ramfis Nieto-Martinez, Ana K Riccio Veliz, Miriam Gutt, Yvette J Kendal, Bertha Veciana, Andrew Ahmann, Diana Aby-Daniel, Farahnaz Joarder, Victoria Morimoto, Carol Sprague, Daisuke Yamashita, Nancy Cady, Nadia Rivera-Eschright, Patricia Kirchhoff, Brianna Morales Gonzalez, Joseph Adducci, Alina Goncharova, Sophia H Hox, Helen Petrovich, Michael Matwichyna, Victoria Jenkins, L Broadwater, Renée R. Ishii, Nina O. Bermudez, Daniel S. Hsia, William T. Cefalu, Frank L. Greenway, Celeste Waguespack, Erin King, Greta Fry, Amber Dragg, Bethany Gildersleeve, Jennifer Arceneaux, Natalie Haynes, Amy Thomassie, Mallory Pavlionis, Brandi Bourgeois, Claire Hazlett, Sunder Mudaliar, Henry Robert, Schafer Boeder, Jeremy Pettus, Elsa Diaz, Daneila Garcia-Acosta, Sarah Maggs, Catherine DeLue, Andrea Stallings, Erick Castro, Sylvia Hernandez, Jonathan Krakoff, Jeffrey M. Curtis, Tina Killean, Meshall Khalid, Erica Joshevama, Enrique Diaz, Denelle Martin, Kaylee Tsingine, Tracey Karshner, Jeanine Albu, F. Xavier Pi-Sunyer, Sylvaine Frances, Carol Maggio, Emily Ellis, Joseph Bastawrose, Xiuqun Gong, Mary Ann Banerji, Phyllis August, Melissa Lee, Daniel Lorber, Brown Necole M., Debra H. Josephson, Lorraine L. Thomas, Maria Tsovian, Ajini Cherian, Marlo H. Jacobson, Motria M. Mishko, Sue M. Kirkman, John B. Buse, Jeanine Dostou, Sriram Machineni, Laura Young, Katherine Bergamo, April Goley, Jeffrey Kerr, Joseph F. Largay, Sonia Guarda, Juanita Cuffee, Dawn Culmer, Rachael Fraser, Hope Almeida, Samantha Coffer, Elizabeth Debnam, Lauren Kiker, Sarah Morton, Kim Josey, Gail Fuller, W. Timothy Garvey, Andrea L. Cherrington, Dana Dyer, Mary Catherine Robertson Lawson, Olivia Griffith, April Agne, Steve McCullars, Robert M. Cohen, Jacqueline Craig, M. Colleen Rogge, Kathryn Burton, Kimberly Kersey, Carla Wilson, Sonia Lipp, Mary Beth Vonder Meulen, Connie Adkins, Tolu Onadeko, Neda Rasouli, Chelsea Baker, Emily Schroeder, Mitra Razzaghi, Corey Lyon, Richard Penaloza, Chantal Underkofler, Rebecca Lorch, Sarah Douglass, Stephanie Steiner, William Sivitz, Erin Cline, Laura K Knosp, Jennifer McConnell, Tamara Lowe, William H. Herman, Rodica Pop-Busui, Meng H. Tan, Catherine Martin, Andrea Waltje, Aimee Katona, Lynn Goodhall, Rebecca Eggleston, Shihchen Kuo, Stefana Bojescu, Stephanie Bule, Nancy Kessler, Elizabeth LaSalle, Kelly Whitley, Elizabeth R. Seaquist, Anne Bantle, Tasma Harindhanavudhi, Anjali Kumar, Bruce Redmon, John Bantle, Mary Coe, Michael Mech, Abdisa Taddese, Lesia Lesne, Shannon Smith, Cyrus Desouza, Lisa Kuechenmeister, Vijay Shivaswamv, Susan Burbach, Maria Grace Rodriguez, Kris Seipel, Alissa Alfred, Ana Laura Morales, Jenna Eggert, Grace Lord, William Taylor, Renee Tillson, David S. Schade, Allen Adolphe, Mark Burge, Elizabeth Duran-Valdez, Janae Martinez, Anna Bancroft, Susan Kunkel, Fadi Ali Jamaleddin Ahmad, Doris Hernandez McGinnis, Benjamin Pucchetti, Elizabeth Scripsick, Amy Zamorano, Ralph A. DeFronzo, Eugenio Cersosimo, Muhammad Abdul-Ghani, Curtis Triplitt, Deanna Juarez, Rosa Irene Garza, Hector Verastiqui, Kathryn Wright, Curtiss Puckett, Philip Raskin, Chanhaeng Rhee, Soma Abraham, Lin Fan Jordan, Serey Sao, Luisa Morton, Oralenda Smith, Laura Osornio Walker, Laura Schnurr-Breen, Rosa Irene Ayala, Robert Brian Kreymer, Daytheon Sturgess, Kristina M Utzschneider, Steven E. Kahn, Lorena Alarcon-Casas Wright, Edward J. Boyko, Elaine C. Tsiai, Dace L. Trence, Subblaxmi Trikudanathan, Basma N. Fattaleh, Brenda K Montgomery, Karen M. Atkinson, Alexandra Kozedub, Tessa Concepcion, Cameron Moak, Nina Prikhodko, Samantha Rhothisen, Tom A. Elasy, Stephanie Martin, Laura Shackelford, Rita Goidel, Nina Hinkle, Cynthia Lovell, Janet Myers, Janie Lipps Hogan, Janet B. McGill, Maamoun Salam, Toni Schweiger, Sarah Kissel, Carol Recklein, Mary Jane Clifton, William Tamborlane, Anne Camp, Barbara Gulanski, Silvio E Inzucchi, Kim Pham, Michele Alguard, Patricia Gatcomb, Katarzyna Lessard, Magalys Perez, Lynne Iannone, Elizabeth Magenheimer, Abmaridel Montosa, William T Cefalu, Judith Fradkin, Henry B. Burch, Andrew Bremer, David M. Nathan, John M. Lachin, Heidi Krause-Steinrauf, Naji Younes, Ionut Bebu, Nicole Butera, CJ Buys, Anna Fagan, Yuping Gao, Alokananda Ghosh, Michaela R. Gramzinski, Stephanie D. Hall, Erin Kazemi, Elizabeth Legowski, Haiyin Liu, Colleen E. Suratt, Mark Tripputi, Alyssa Arey, Michael Backman, Joel Bethepu, Claire Lund, Pam Mangat Dhaliwal, Paula McGee, Emily Mesimer, Lisa Ngo, Michael Steffes, Jesse Seegmiller, Amy Saenger, Valerie Arends, Deanna Gabrielson, Todd Conner, Stuart Warren, Jolene Day, Jeffrey Huminik, Alexandra Scrymgeour, Elsayed Z. Soliman, Yashashwi Pokharel, Zhu-Ming Zhang, Charles Campbell, Julie Hu, Lisa Keasler, Susan Hensley, Yabing Li, Rada Mihalcea, Do June Min, Veronica Perez-Rosas, Lisa Prosser, Kenneth Resnicow, Wen Ye, Hui Shao, Ping Zhang, Jose Luchsinger, Danurys Sanchez, Stephanie Assuras, Erik Groessl, Fatema Sakha, Helen Chong, Naomi Hillery, Ivan Abdouch, Gul Bahityar, Paula Brantley, Frances E. Broyles, Gay Canaris, Paul Copeland, Jeri J. Craine, Warren L. Fein, Agnieska Gliwa, Lisel M. Hope, Melissa S. Lee, Rebecca Meiners, Vaughn Meiners, Hollis O'Neal, James E. Park, Alan Sacerdote, Edward Sledge, Lisa Soni, Jeanne Steppel-Reznik, Alexander Turchin
Journal: JAMA Internal Medicine (2023)

Importance Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. Objective To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. Design, Setting, and Participants A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A 1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m 2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Interventions Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA 1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Main Outcomes and Measures Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m 2 , 40% decrease in eGFR to less than 60 mL/min/1.73 m 2 , doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Results Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA 1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m 2 ; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was −2.03 (95% CI, −2.20 to −1.86) mL/min/1.73 m 2 per year for patients receiving sitagliptin; glimepiride, −1.92 (95% CI, −2.08 to −1.75) mL/min/1.73 m 2 per year; liraglutide, −2.08 (95% CI, −2.26 to −1.90) mL/min/1.73 m 2 per year; and insulin glargine, −2.02 (95% CI, −2.19 to −1.84) mL/min/1.73 m 2 per year ( P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) ( P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. Conclusions and Relevance In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. Trial Registration ClinicalTrials.gov Identifier: NCT01794143